Capastat Sulfate is a polypeptide antibiotic isolated from Streptomyces capreolus. It is a complex of 4 microbiologically active components which have been characterized in part; however, complete structural determination of all the components has not been established.

Capreomycin is supplied as the disulfate salt and is soluble in water. In complete solution, it is almost colorless.

Each vial contains the equivalent of 1 g capreomycin activity.

The structural formula is as follows:

Last updated on RxList: 9/4/2008

Capastat Sulfate, which is to be used concomitantly with other appropriate antituberculosis agents, is indicated in pulmonary infections caused by capreomycin-susceptible strains of M. tuberculosis when the primary agents (isoniazid, rifampin, ethambutol, aminosalicylic acid, and streptomycin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.

Susceptibility studies should be performed to determine the presence of a capreomycin­susceptible strain of M. tuberculosis.

Capastat Sulfate may be administered intramuscularly or intravenously following reconstitution. Reconstitution is achieved by dissolving the vial contents (1 g) in 2 mL of 0.9% Sodium Chloride Injection or Sterile Water for Injection. Two to 3 minutes should be allowed for complete dissolution.

Intravenously - For intravenous infusion, reconstituted Capastat Sulfate should be diluted in 100 mL of 0.9% Sodium Chloride Injection and administered over 60 minutes.

Intramuscularly - Reconstituted Capastat Sulfate should be given by deep intramuscular injection into a large muscle mass, since superficial injection may be associated with increased pain and the development of sterile abscesses.

For administration of a 1-g dose, the entire contents of the vial should be given. For doses lower than 1 g, the following dilution table may be used.

DILUTION TABLE

Diluent Added to 1-g, 10-mL Vial	Volume of Capastat Sulfate Solution	Concentration (Approx)
2.15 mL	2.85 mL	370 mg*/mL
2.63 mL	3.33 mL	315 mg*/mL
3.3 mL	4 mL	260 mg*/mL
4.3 mL	5 mL	210 mg*/mL
* Equivalent to capreomycin activity. Approximated concentration takes into account the retention volume.

The solution may acquire a pale straw color and darken with time, but this is not associated with loss of potency or the development of toxicity. After reconstitution, all solutions of Capastat Sulfate may be stored for up to 24 hours under refrigeration.

Capreomycin is always administered in combination with at least 1 other antituberculosis agent to which the patient's strain of tubercle bacilli is susceptible. The usual dose is 1 g daily (not to exceed 20 mg/kg/day) given intramuscularly or intravenously for 60 to 120 days, followed by 1 g by either route 2 or 3 times weekly. (Note - Therapy for tuberculosis should be maintained for 12 to 24 months. If facilities for administering injectable medication are not available, a change to appropriate oral therapy is indicated on the patient's release from the hospital.)

Patients with reduced renal function should have dosage reduction based on creatinine clearance using the guidelines included in Table 1. These dosages are designed to achieve a mean steady-state capreomycin level of 10 µg/mL.

Table 1. Estimated Dosages to Attain Mean Steady-State Serum Capreomycin Concentration of 10 µg/mL (Based on Creatinine Clearance)

CrCl (mL/min)	Capreomycin Clearance (L/kg/h x 10-2)	Half-life (hours)	Dosea (mg/kg) for the Following Dosing Intervals
			24 h	48 h	72 h
0	0.54	55.5	1.29	2.58	3.87
10	1.01	29.4	2.43	4.87	7.30
20	1.49	20.0	3.58	7.16	10.7
30	1.97	15.1	4.72	9.45	14.2
40	2.45	12.2	5.87	11.7
50	2.92	10.2	7.01	14.0
60	3.40	8.8	8.16
80	4.35	6.8	10.4b
100	5.31	5.6	12.7b
110	5.78	5.2	13.9b
a For patients with renal impairment, initial maintenance dose estimates are given for optional dosing intervals; longer dosing intervals are expected to provide greater peak and lower trough serum capreomycin levels than shorter dosing intervals. b The usual dosage for patients with normal renal function is 1000 mg daily, not to exceed 20 mg/kg/day, for 60 to120 days, then 1000 mg 2 to 3 times weekly.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Capastat® Sulfate, Capreomycin for Injection, USP, is available in:

Vials: 1 g*, 10 mL size (No. 718) (1s) NDC 0002-1485-01

Store at controlled room temperature 15° to 30°C (59° to 86°F) prior to reconstitution.

*Equivalent to capreomycin activity.

Literature revised January 14, 2008. Eli Lilly and Company, Indianapolis, IN 46285, USA. FDA Rev date: 7/24/2008

Last updated on RxList: 9/4/2008

Nephrotoxicity: In 36% of 722 patients treated with Capastat Sulfate, elevation of the BUN above 20 mg/100 mL has been observed. In many instances, there was also depression of PSP excretion and abnormal urine sediment. In 10% of this series, the BUN elevation exceeded 30 mg/100 mL.

Toxic nephritis was reported in 1 patient with tuberculosis and portal cirrhosis who was treated with Capastat Sulfate (1 g) and aminosalicylic acid daily for 1 month. This patient developed renal insufficiency and oliguria and died. Autopsy showed subsiding acute tubular necrosis.

Electrolyte disturbances including hypokalemia, hypomagnesemia and hypocalcemia, sometimes serious in nature, have been reported.

Ototoxicity: Subclinical auditory loss was noted in approximately 11% of 722 patients undergoing treatment with Capastat Sulfate. This was a 5- to 10-decibel loss in the 4000- to 8000-CPS range. Clinically apparent hearing loss occurred in 3% of the 722 subjects. Some audiometric changes were reversible. Other cases with permanent loss were not progressive following withdrawal of Capastat Sulfate.

Tinnitus and vertigo have occurred.

Liver: Serial tests of liver function have demonstrated a decrease in BSP excretion without change in AST (SGOT) or ALT (SGPT) in the presence of preexisting liver disease. Abnormal results in liver function tests have occurred in many persons receiving Capastat Sulfate in combination with other antituberculosis agents that also are known to cause changes in hepatic function. The role of Capastat Sulfate in producing these abnormalities is not clear; however, periodic determinations of liver function are recommended.

Blood: Leukocytosis and leukopenia have been observed. The majority of patients treated have had eosinophilia exceeding 5% while receiving daily injections of Capastat Sulfate. This has subsided with reduction of the Capastat Sulfate dosage to 2 or 3 g weekly.

Pain and induration at the injection site have been observed. Excessive bleeding at the injection site has been reported. Sterile abscesses have been noted. Rare cases of thrombocytopenia have been reported.

Hypersensitivity:Urticaria and maculopapular skin rashes associated in some cases with febrile reactions have been reported when Capastat Sulfate and other antituberculosis drugs were given concomitantly.

No information provided.

Last updated on RxList: 9/4/2008

No information provided.

General

Audiometric measurements and assessment of vestibular function should be performed prior to initiation of therapy with Capastat Sulfate and at regular intervals during treatment.

Renal injury, with tubular necrosis, elevation of the blood urea nitrogen (BUN) or serum creatinine, and abnormal urinary sediment, has been noted. Slight elevation of the BUN and serum creatinine has been observed in a significant number of patients receiving prolonged therapy. The appearance of casts, red cells, and white cells in the urine has been noted in a high percentage of these cases. Elevation of the BUN above 30 mg/100 mL or any other evidence of decreasing renal function with or without a rise in BUN levels calls for careful evaluation of the patient, and the dosage should be reduced or the drug completely withdrawn. The clinical significance of abnormal urine sediment and slight elevation in the BUN (or serum creatinine) observed during long-term therapy with Capastat Sulfate has not been established.

The peripheral neuromuscular blocking action that has been attributed to other polypeptide antibiotics (colistin sulfate, polymyxin A sulfate, paromomycin, and viomycin) and to aminoglycoside antibiotics (streptomycin, dihydrostreptomycin, neomycin, and kanamycin) has been studied with Capastat Sulfate. A partial neuromuscular blockade was demonstrated after large intravenous doses of Capastat Sulfate. This action was enhanced by ether anesthesia (as has been reported for neomycin) and was antagonized by neostigmine.

Caution should be exercised in the administration of antibiotics, including Capastat Sulfate, to any patient who has demonstrated some form of allergy, particularly to drugs.

Laboratory Tests

Regular tests of renal function should be made throughout the period of treatment, and reduced dosage should be employed in patients with known or suspected renal impairment.

Renal function studies should be made both before therapy with Capastat Sulfate is started and on a weekly basis during treatment.

Since hypokalemia, hypomagnesemia and hypocalcemia may occur during therapy, these serum electrolyte levels should be determined frequently.

For neuromuscular blocking action of this drug, see PRECAUTIONS, General.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been performed to determine potential for carcinogenicity, mutagenicity, or impairment of fertility.

Usage in Pregnancy - Pregnancy Category C

Capastat Sulfate has been shown to be teratogenic in rats when given in doses 3 1/2 times the human dose. There are no adequate and well-controlled studies in pregnant women. Capastat Sulfate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Boxed Warnings and Animal Pharmacology).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Capastat Sulfate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see Boxed Warnings).

Geriatric Use

Clinical studies of Capastat Sulfate did not analyze the safety and efficacy of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Capastat Sulfate is known to be substantially excreted by the kidney (see CLINICAL PHARMACOLOGY), and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS, Laboratory Tests). Patients with reduced renal function should have dosage reduction based on creatinine clearance using the guidelines included in Table 1 (see DOSAGE AND ADMINISTRATION).

The geriatric population is also more likely to have impaired hearing at baseline. Audiometric measurements and assessment of vestibular function should be performed prior to initiation of therapy with Capastat Sulfate and at regular intervals during treatment (see PRECAUTIONS, General).

Last updated on RxList: 9/4/2008

Signs and Symptoms

Nephrotoxicity following the parenteral administration of Capastat Sulfate is most closely related to the area under the curve of the serum concentration versus time graph. The elderly patient, patients with abnormal renal function or dehydration, and patients receiving other nephrotoxic drugs are at much greater risk for developing acute tubular necrosis.

Damage to the auditory and vestibular divisions of cranial nerve VIII has been associated with Capastat Sulfate given to patients with abnormal renal function or dehydration and in those receiving medications with additive auditory toxicities. These patients often experience dizziness, tinnitus, vertigo, and a loss of high-tone acuity.

Neuromuscular blockage or respiratory paralysis may occur following rapid intravenous infusion.

If capreomycin is ingested, toxicity would be unlikely because it is poorly absorbed (less than 1%) from an intact gastrointestinal system.

Hypokalemia, hypocalcemia, hypomagnesemia, and an electrolyte disturbance resembling Bartter's syndrome have been reported The subcutaneous median lethal dose in mice was 514 mg/kg.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient's airway and maintain, within acceptable limits, the patient's Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal.

Patients who have received an overdose of capreomycin and have normal renal function should be carefully hydrated to maintain a urine output of 3 to 5 mL/kg/h. Fluid balance, electrolytes, and creatinine clearance should be carefully monitored.

Hemodialysis may be effectively used to remove capreomycin in patients with significant renal disease.

Capastat Sulfate is contraindicated in patients who are hypersensitive to capreomycin.

Last updated on RxList: 9/4/2008

Human Pharmacology

Capreomycin is not absorbed in significant quantities from the gastrointestinal tract and must be administered parenterally. In 2 studies of 10 patients each, peak serum concentrations following 1 g of capreomycin given intramuscularly were achieved 1 to 2 hours after administration, and average peak levels reached were 28 and 32 µg/mL respectively (range, 20 to 47 µg/mL). Low serum concentrations were present at 24 hours. However, 1 g of capreomycin daily for 30 days or more produced no significant accumulation in subjects with normal renal function. Two patients with marked reduction of renal function had high serum concentrations 24 hours after administration of the drug. When a 1-g dose of capreomycin was given intramuscularly to normal volunteers, 52% was excreted in the urine within 12 hours.

Lehmann, et al, examined the pharmacokinetics of single dose capreomycin (1.0 g) administered intramuscularly and by intravenous infusion (1 hour) in 6 healthy volunteers. The area under the serum concentration versus time curve was similar for the two routes of administration. Capreomycin peak concentrations after intravenous infusion were 30 ± 47% higher than after intramuscular administration.^1,2

Paper chromatographic studies indicated that capreomycin is excreted essentially unaltered. Urine concentrations averaged 1.68 mg/mL (average urine volume, 228 mL) during the 6 hours following a 1-g dose.

Microbiology

Capreomycin is active against strains of Mycobacterium tuberculosis found in humans.

Susceptibility Tests

The in vitro susceptibility of strains of M. tuberculosis to capreomycin varies with the media and techniques employed. In general, the minimum inhibitory concentrations for M. tuberculosis are lowest in liquid media that are free of egg protein (7H10 or Dubos) and range from 1 to 5 µg/mL when the indirect method is used. Comparable inhibitory concentrations are obtained when 7H10 agar is used for direct susceptibility testing. When indirect susceptibility tests are performed on standard tube slants with 7H10 media, susceptible strains are inhibited by 10 to 25 µg/mL capreomycin. Egg-containing media, such as Löwenstein-Jensen or ATS, require concentrations of 25 to 50 µg/mL to inhibit susceptible strains.

Cross-Resistance

Frequent cross-resistance occurs between capreomycin and viomycin. Varying degrees of cross-resistance between capreomycin and kanamycin and neomycin have been reported. No cross-resistance has been observed between capreomycin and isoniazid, aminosalicylic acid, cycloserine, streptomycin, ethionamide, or ethambutol.

Animal Pharmacology

In addition to renal and cranial nerve VIII toxicity demonstrated in animal toxicology studies, cataracts developed in 2 dogs on doses of 62 mg/kg and 100 mg/kg for prolonged periods.

In teratology studies, a low incidence of "wavy ribs" was noted in litters of female rats treated with daily doses of 50 mg/kg or more of capreomycin.

REFERENCES

1. Lehmann CR, Garrett LE, Winn RE, Springberg PD, Vicks S, Porter DK, Pierson WP, Wolny JD, Brier GL, Black HR. Capreomycin kinetics in renal impairment and clearance by hemodialysis. Am Rev Respir Dis 1988;138/5:1312-3.

2. Unpublished data on file at Lilly.

Last updated on RxList: 9/4/2008

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 9/4/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CAPREOMYCIN - INJECTION

(KAP-ree-oh-MY-sin)

COMMON BRAND NAME(S): Capastat Sulfate

WARNING: Use capreomycin with extreme caution in people with hearing or kidney problems and in those using other drugs that may cause hearing or kidney problems (see Drug Interactions section).

Other injectable medications used to treat tuberculosis (e.g., streptomycin) should not be used with capreomycin because they will increase the risk of hearing and kidney problems.

USES: This medication is used with other drugs to treat tuberculosis (TB) infections. Capreomycin belongs to a class of drugs known as antibiotics. It is believed to work by preventing the growth of the bacteria that causes TB.

HOW TO USE: This medication is given by injection into a muscle or infused into a vein over 1 hour, usually by a health care professional. It is usually given once a day for 2 to 4 months then reduced to 2 or 3 times a week depending on your condition and response to treatment, or use as directed by your doctor. Before using this product, check it visually for particles. When mixed, this medication may be nearly colorless or very pale yellow. The color may darken over time, but this does not make this medication less effective. If the liquid has particles or has changed to any other color than pale or dark yellow, do not use it. Dosage is based on your medical conditions, kidney function, and response to treatment.

If you are getting this medication by injection into a muscle, remember to change the injection site with each dose to prevent irritation. Also, inject this medication into a large muscle such as the buttock or thigh to lessen pain from the injection.

Continue to use this medication until the full prescribed amount is finished, even if symptoms disappear. Stopping the medication too early may result in a return of the infection. It may be necessary to continue treatment for TB for 1 to 2 years. If needed, your doctor may switch you to a drug for this same condition that can be taken by mouth.

This medication works best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it on the same day(s) of the week or at the same time each day, depending on your doctor's instructions. If you are taking this medication several times a week, it may help to mark your calendar with a reminder.

Do not use more or less of this drug than prescribed or stop using it (or other TB medicines) even for a short time unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause the amount of TB bacteria to increase, make the infection more difficult to treat (resistant), or worsen side effects. If TB becomes resistant to this medication, it might also become resistant to other TB medications.

If you are giving yourself injections at home, make sure you learn how to prepare and inject this medication properly. Ask your doctor, pharmacist, or nurse any questions you may have about how to give yourself this medication. Learn how to store and discard needles, medical supplies, and any unused medication safely. Never reuse needles or syringes. Consult your pharmacist.

Tell your doctor if your condition persists or worsens.

SIDE EFFECTS: Pain, irritation, or skin hardening at the injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: change in the amount of urine, ringing in the ears, trouble hearing, dizziness.

Tell your doctor immediately if any of these rare but very serious side effects occur: muscle weakness/cramps, irregular heartbeat, easy bleeding/bruising.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using capreomycin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, hearing trouble, dehydration, liver disease, a certain muscle disease (myasthenia gravis), Parkinson's disease.

This drug may make you dizzy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at a greater risk for side effects while using this drug.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that may harm either the kidneys or hearing (e.g., amphotericin B, colistin, cidofovir, polymyxin, vancomycin, aminoglycosides such as amikacin/gentamicin/kanamycin/tobramycin), certain anesthetics, live bacterial vaccines.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe dizziness, ringing in the ears, loss of ability to hear high sounds, trouble breathing, change in the amount of urine.

NOTES: If your doctor tells you that you are contagious, then you must avoid contact with others to prevent the spread of your TB infection.

Laboratory and/or medical tests (e.g., TB cultures, kidney function, hearing tests, liver function, chest X-rays, potassium blood levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: It is important to use each dose as scheduled. If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. If you miss more than one dose, contact your health care professional to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store unopened vials at room temperature between 59-86 degrees F (15-30 degrees C) away from light and heat. Once mixed the medication is good for 24 hours if refrigerated between 36-46 degrees F (2-8 degrees C). Discard the mixed medication if it is not used within this time. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.